XB-ART-13374
EMBO J
1999 Mar 15;186:1660-72. doi: 10.1093/emboj/18.6.1660.
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A leucine-rich nuclear export signal in the p53 tetramerization domain: regulation of subcellular localization and p53 activity by NES masking.
Stommel JM
,
Marchenko ND
,
Jimenez GS
,
Moll UM
,
Hope TJ
,
Wahl GM
.
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Appropriate subcellular localization is crucial for regulating p53 function. We show that p53 export is mediated by a highly conserved leucine-rich nuclear export signal (NES) located in its tetramerization domain. Mutation of NES residues prevented p53 export and hampered tetramer formation. Although the p53-binding protein MDM2 has an NES and has been proposed to mediate p53 export, we show that the intrinsic p53 NES is both necessary and sufficient for export. This report also demonstrates that the cytoplasmic localization of p53 in neuroblastoma cells is due to its hyperactive nuclear export: p53 in these cells can be trapped in the nucleus by the export-inhibiting drug leptomycin B or by binding a p53-tetramerization domain peptide that masks the NES. We propose a model in which regulated p53 tetramerization occludes its NES, thereby ensuring nuclear retention of the DNA-binding form. We suggest that attenuation of p53 function involves the conversion of tetramers into monomers or dimers, in which the NES is exposed to the proteins which mediate their export to the cytoplasm.
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Species referenced: Xenopus
Genes referenced: mdm2 tp53
References [+] :
Aladjem,
ES cells do not activate p53-dependent stress responses and undergo p53-independent apoptosis in response to DNA damage.
1998, Pubmed
Aladjem, ES cells do not activate p53-dependent stress responses and undergo p53-independent apoptosis in response to DNA damage. 1998, Pubmed
Askjaer, The specificity of the CRM1-Rev nuclear export signal interaction is mediated by RanGTP. 1998, Pubmed
Bachelerie, Nuclear export signal of IkappaBalpha interferes with the Rev-dependent posttranscriptional regulation of human immunodeficiency virus type I. 1997, Pubmed
Bischoff, Human p53 is phosphorylated by p60-cdc2 and cyclin B-cdc2. 1990, Pubmed
Bogerd, Protein sequence requirements for function of the human T-cell leukemia virus type 1 Rex nuclear export signal delineated by a novel in vivo randomization-selection assay. 1996, Pubmed
Bosari, p53 gene mutations, p53 protein accumulation and compartmentalization in colorectal adenocarcinoma. 1995, Pubmed
Cheng, Zebrafish (Danio rerio) p53 tumor suppressor gene: cDNA sequence and expression during embryogenesis. 1997, Pubmed
Chernov, Stabilization and activation of p53 are regulated independently by different phosphorylation events. 1998, Pubmed
Chernova, MYC abrogates p53-mediated cell cycle arrest in N-(phosphonacetyl)-L-aspartate-treated cells, permitting CAD gene amplification. 1998, Pubmed
Clore, Refined solution structure of the oligomerization domain of the tumour suppressor p53. 1995, Pubmed
Crook, Transcriptional activation by p53 correlates with suppression of growth but not transformation. 1994, Pubmed
David-Pfeuty, Cell cycle-dependent regulation of nuclear p53 traffic occurs in one subclass of human tumor cells and in untransformed cells. 1996, Pubmed
Fischer, The HIV-1 Rev activation domain is a nuclear export signal that accesses an export pathway used by specific cellular RNAs. 1995, Pubmed
Fornerod, CRM1 is an export receptor for leucine-rich nuclear export signals. 1997, Pubmed , Xenbase
Freedman, Nuclear export is required for degradation of endogenous p53 by MDM2 and human papillomavirus E6. 1998, Pubmed
Friedman, The p53 protein is an unusually shaped tetramer that binds directly to DNA. 1993, Pubmed
Fritsche, Induction of nuclear accumulation of the tumor-suppressor protein p53 by DNA-damaging agents. 1993, Pubmed
Gerace, Nuclear export signals and the fast track to the cytoplasm. 1995, Pubmed
Görlich, Nucleocytoplasmic transport. 1996, Pubmed
Hainaut, Analysis of p53 quaternary structure in relation to sequence-specific DNA binding. 1994, Pubmed
Halazonetis, Conformational shifts propagate from the oligomerization domain of p53 to its tetrameric DNA binding domain and restore DNA binding to select p53 mutants. 1993, Pubmed
Haupt, Mdm2 promotes the rapid degradation of p53. 1997, Pubmed
Heyman, 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor. 1992, Pubmed
Huang, Conic: a fast renderer for space-filling molecules with shadows. 1991, Pubmed
Hupp, Regulation of the specific DNA binding function of p53. 1992, Pubmed
Hupp, Allosteric activation of latent p53 tetramers. 1994, Pubmed
Ishioka, Oligomerization is not essential for growth suppression by p53 in p53-deficient osteosarcoma Saos-2 cells. 1997, Pubmed
Jeffrey, Crystal structure of the tetramerization domain of the p53 tumor suppressor at 1.7 angstroms. 1995, Pubmed
Jones, Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. 1995, Pubmed
Kaghad, Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. 1997, Pubmed
Kastan, Participation of p53 protein in the cellular response to DNA damage. 1991, Pubmed
Khokhlatchev, Phosphorylation of the MAP kinase ERK2 promotes its homodimerization and nuclear translocation. 1998, Pubmed
Kim, Characterization of the nuclear export signal of human T-cell lymphotropic virus type 1 Rex reveals that nuclear export is mediated by position-variable hydrophobic interactions. 1996, Pubmed
Klotzsche, Cytoplasmic retention of mutant tsp53 is dependent on an intermediate filament protein (vimentin) scaffold. 1998, Pubmed
Ko, p53: puzzle and paradigm. 1996, Pubmed
Komarova, Intracellular localization of p53 tumor suppressor protein in gamma-irradiated cells is cell cycle regulated and determined by the nucleus. 1997, Pubmed
Kubbutat, Regulation of p53 stability by Mdm2. 1997, Pubmed
Kussie, Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. 1996, Pubmed
Lee, Solution structure of the tetrameric minimum transforming domain of p53. 1994, Pubmed
Levine, p53, the cellular gatekeeper for growth and division. 1997, Pubmed
Liang, Cooperation of a single lysine mutation and a C-terminal domain in the cytoplasmic sequestration of the p53 protein. 1998, Pubmed
Lin, Several hydrophobic amino acids in the p53 amino-terminal domain are required for transcriptional activation, binding to mdm-2 and the adenovirus 5 E1B 55-kD protein. 1994, Pubmed
Linke, A reversible, p53-dependent G0/G1 cell cycle arrest induced by ribonucleotide depletion in the absence of detectable DNA damage. 1996, Pubmed
Lomax, Characterization of p53 oligomerization domain mutations isolated from Li-Fraumeni and Li-Fraumeni like family members. 1998, Pubmed
Lou, Novel patterns of p53 abnormality in breast cancer from Taiwan: experience from a low-incidence area. 1997, Pubmed
Lu, Ultraviolet radiation, but not gamma radiation or etoposide-induced DNA damage, results in the phosphorylation of the murine p53 protein at serine-389. 1998, Pubmed
Martinez, Free radicals generated by ionizing radiation signal nuclear translocation of p53. 1997, Pubmed
Mateu, Nine hydrophobic side chains are key determinants of the thermodynamic stability and oligomerization status of tumour suppressor p53 tetramerization domain. 1998, Pubmed
McLure, How p53 binds DNA as a tetramer. 1998, Pubmed
Middeler, The tumor suppressor p53 is subject to both nuclear import and export, and both are fast, energy-dependent and lectin-inhibited. 1997, Pubmed
Moll, Two distinct mechanisms alter p53 in breast cancer: mutation and nuclear exclusion. 1992, Pubmed
Moll, Wild-type p53 protein undergoes cytoplasmic sequestration in undifferentiated neuroblastomas but not in differentiated tumors. 1995, Pubmed
Moll, Cytoplasmic sequestration of wild-type p53 protein impairs the G1 checkpoint after DNA damage. 1996, Pubmed
Momand, The MDM2 gene amplification database. 1998, Pubmed
Moser, Mouse-human heterokaryon analysis with a 33258 Hoechst-Giemsa technique. 1975, Pubmed
Norris, A fluorescent p53GFP fusion protein facilitates its detection in mammalian cells while retaining the properties of wild-type p53. 1997, Pubmed
Oliner, Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53. 1993, Pubmed
Osada, Cloning and functional analysis of human p51, which structurally and functionally resembles p53. 1998, Pubmed
Ossareh-Nazari, Evidence for a role of CRM1 in signal-mediated nuclear protein export. 1997, Pubmed
Ostermeyer, Cytoplasmically sequestered wild-type p53 protein in neuroblastoma is relocated to the nucleus by a C-terminal peptide. 1996, Pubmed
Paulson, Gene amplification in a p53-deficient cell line requires cell cycle progression under conditions that generate DNA breakage. 1998, Pubmed
Pfeifer, Mutagenesis in the P53 gene. 1997, Pubmed
Pietenpol, Sequence-specific transcriptional activation is essential for growth suppression by p53. 1994, Pubmed
Price, Cdk2 kinase phosphorylates serine 315 of human p53 in vitro. 1995, Pubmed
Roth, Nucleo-cytoplasmic shuttling of the hdm2 oncoprotein regulates the levels of the p53 protein via a pathway used by the human immunodeficiency virus rev protein. 1998, Pubmed
Sakaguchi, Phosphorylation of serine 392 stabilizes the tetramer formation of tumor suppressor protein p53. 1997, Pubmed
Schlamp, Nuclear exclusion of wild-type p53 in immortalized human retinoblastoma cells. 1997, Pubmed
Shaulsky, Nuclear accumulation of p53 protein is mediated by several nuclear localization signals and plays a role in tumorigenesis. 1990, Pubmed
Shaulsky, Subcellular distribution of the p53 protein during the cell cycle of Balb/c 3T3 cells. 1990, Pubmed
Sherr, Tumor surveillance via the ARF-p53 pathway. 1998, Pubmed
Shieh, DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. 1997, Pubmed
Soussi, Structural aspects of the p53 protein in relation to gene evolution: a second look. 1996, Pubmed
Stenmark-Askmalm, Cellular accumulation of p53 protein: an independent prognostic factor in stage II breast cancer. 1994, Pubmed
Sun, Prognostic significance of cytoplasmic p53 oncoprotein in colorectal adenocarcinoma. 1992, Pubmed
Tarunina, Selective loss of endogenous p21waf1/cip1 induction underlies the G1 checkpoint defect of monomeric p53 proteins. 1996, Pubmed
Ueda, Functional inactivation but not structural mutation of p53 causes liver cancer. 1995, Pubmed
Ullman, Nuclear export receptors: from importin to exportin. 1997, Pubmed
Varley, A previously undescribed mutation within the tetramerisation domain of TP53 in a family with Li-Fraumeni syndrome. 1996, Pubmed
Wahl, Maintaining genetic stability through TP53 mediated checkpoint control. 1997, Pubmed
Wang, p53 domains: structure, oligomerization, and transformation. 1994, Pubmed
Waterman, The dihedral symmetry of the p53 tetramerization domain mandates a conformational switch upon DNA binding. 1995, Pubmed
Wen, Identification of a signal for rapid export of proteins from the nucleus. 1995, Pubmed
Wolff, Leptomycin B is an inhibitor of nuclear export: inhibition of nucleo-cytoplasmic translocation of the human immunodeficiency virus type 1 (HIV-1) Rev protein and Rev-dependent mRNA. 1997, Pubmed
Wu, The p53-mdm-2 autoregulatory feedback loop. 1993, Pubmed
Yang, Control of cyclin B1 localization through regulated binding of the nuclear export factor CRM1. 1998, Pubmed , Xenbase
Zhu, Intramolecular masking of nuclear import signal on NF-AT4 by casein kinase I and MEKK1. 1998, Pubmed